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Date of Award
Doctor of Philosophy (PhD)
Malaria remains one of the deadliest infectious diseases worldwide, and efforts to combat it require novel insights into diagnostics, vector transmission, and drug inhibitor targets. Previous studies suggest that malaria infection causes hosts to preferentially attract the transmission vector, the Anopheles mosquito, but the mechanism and wider implication of these findings were not known. By analyzing the headspace above malaria parasite cultures, we identified several molecules that might engender mosquito attraction. We demonstrated that several of these molecules activate mosquito odorant receptors, including the known plant-emitted mosquito attractant _-pinene. During patient studies involving two independent pediatric clinical populations from Malawi, we observed that _-pinene and the related compound 3-carene are present at higher concentrations in the breath of infected patients versus uninfected patients. Furthermore, initial analysis of sweat samples identified additional malaria-induced volatile profile changes. These results provide a viable mechanism by which infection causes increased mosquito attraction, with potential applications for creating superior lures for mosquito vector elimination campaigns. With the same two populations, we evaluated two different methods for breath collection. We found that inert sampling bags have superior performance to the inert Bio-VOC syringe. Fascinatingly, using data from the sampling bag study, we discovered that patient breath contains volatile biomarkers that can distinguish between infected and uninfected patients. Ascertaining that malaria breath biomarkers exist paves the way for future research on new non-invasive breath diagnostic tools.
The metabolic fate of isoprenoids, the chemical class to which _-pinene and 3-carene belong, also provides potential targets for antimalarial drugs. Previous research has shown prenylation, the attachment of specific isoprenoid groups to proteins to facilitate proper localization and function, is an essential pathway in the parasite. However, the protein prenylation substrates for the malaria parasite were not known. Using a novel metabolic labelling strategy with an alkyne modified prenyl analogue, we determined the entire complement of parasite prenylated proteins. These findings will aid ongoing efforts to design inhibitors against the parasite enzymes mediating prenylation. Initial evidence of a new series of parasite prenyl transferase, specifically farnesyl transferase, inhibitors is presented as well.
Chair and Committee
Audrey R. Odom John
Jeffrey P. Henderson, Daniel S. Ory, Baranidharan Raman, L. David Sibley,
Schaber, Chad Louis, "Breath biomarkers and an expanded role for isoprenoids in Plasmodium falciparum" (2018). Arts & Sciences Electronic Theses and Dissertations. 1651.
Available for download on Sunday, June 21, 2020